Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner

Atsushi Hirao, Alison Cheung, Gordon Duncan, Pierre Marie Girard, Andrew J. Elia, Andrew Wakeham, Hitoshi Okada, Talin Sarkissian, Jorge A. Wong, Takashi Sakai, Elisa De Stanchina, Robert G. Bristow, Toshio Suda, Scott W. Lowe, Penny A. Jeggo, Stephen J. Elledge, Tak W. Mak

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Abstract

In response to ionizing radiation (IR), the tumor suppressor p53 is stabilized and promotes either cell cycle arrest or apoptosis. Chk2 activated by IR contributes to this stabilization, possibly by direct phosphorylation. Like p53, Chk2 is mutated in patients with Li-Fraumeni syndrome. Since the ataxia telangiectasia mutated (ATM) gene is required for IR-induced activation of Chk2, it has been assumed that ATM and Chk2 act in a linear pathway leading to p53 activation. To clarify the role of Chk2 in tumorigenesis, we generated genetargeted Chk2-deficient mice. Unlike ATM-/- and p53-/- mice, Chk2-/- mice do not spontaneously develop tumors, although Chk2 does suppress 7,12-dimethylbenzanthracene-induced skin tumors. Tissues from Chk2-/- mice, including those from the thymus, central nervous system, fibroblasts, epidermis, and hair follicles, show significant defects in IR-induced apoptosis or impaired G1/S arrest. Quantitative comparison of the G1/S checkpoint, apoptosis, and expression of p53 proteins in Chk2-/- versus ATM-/- thymocytes suggested that Chk2 can regulate p53-dependent apoptosis in an ATM-independent manner. IR-induced apoptosis was restored in Chk2-/- thymocytes by reintroduction of the wild-type Chk2 gene but not by a Chk2 gene in which the sites phosphorylated by ATM and ataxia telangiectasia and rad3+ related (ATR) were mutated to alanine. ATR may thus selectively contribute to p53-mediated apoptosis. These data indicate that distinct pathways regulate the activation of p53 leading to cell cycle arrest or apoptosis.

Original languageEnglish
Pages (from-to)6521-6532
Number of pages12
JournalMolecular and cellular biology
Volume22
Issue number18
DOIs
Publication statusPublished - 2002 Sep 1

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Hirao, A., Cheung, A., Duncan, G., Girard, P. M., Elia, A. J., Wakeham, A., Okada, H., Sarkissian, T., Wong, J. A., Sakai, T., De Stanchina, E., Bristow, R. G., Suda, T., Lowe, S. W., Jeggo, P. A., Elledge, S. J., & Mak, T. W. (2002). Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner. Molecular and cellular biology, 22(18), 6521-6532. https://doi.org/10.1128/MCB.22.18.6521-6532.2002